DTPA monoamides for MRI

ABSTRACT

Chelate compounds of general formula I ##STR1## wherein X is a hydrogen atom and/or a metal ion equivalent of an element of atomic numbers 21-29, 31, 32, 37-40, 42-44, 49 or 57-83, and 
     Z 1 , Z 2 , R 1 , R 2 , R 3  and R 4  are as defined herein, as well as their salts with inorganic and/or organic bases, amino acids or amino acid amides, are valuable pharmaceutical agents, e.g., for NMR imaging.

This is a division of application Ser. No. 08/228,524 filed Apr. 15,1994, which is a continuation of Ser. No. 07/681,682, filed Apr. 8, 1991(abandoned).

The invention relates to new diethylenetriaminepentaacetic acid (DTPA)monoamides, DTPA monoamide complexes and complex salts, agentscontaining these compounds, their use in the NMR diagnosis as well asthe process for the production of these compounds and agents.

At the beginning of the fifties, metal complexes were already underconsideration as contrast media for radiology. But the compounds used atthat time were so toxic that a use in humans was out of the question. Itwas therefore really surprising that certain complex salts provedsufficiently compatible so that a routine use in humans for diagnosticpurposes could be taken into consideration. As a first representative ofthis family of substances, the dimeglumine salt of the Gd DTPA(gadolinium(III) complex of diethylenetriaminepentaacetic acid)described in the European patent application with publication number71564 has proven itself very well as a contrast medium for nuclear spintomography. It has been registered worldwide as the first NMR diagnosticagent under the name Magnevist®.

Magnevist® is especially well-suited for the diagnosis of pathologicalareas (e.g., inflammations, tumors, infarctions, etc.). Afterintravenous injection, the compound spreads extracellularly and iseliminated by glomerular secretion through the kidneys. Passage ofintact cell membranes and extrarenal elimination are practically notobserved.

Contrast media, which exhibit at least a partially extrarenalelimination, were desirable especially for patients with limited kidneyfunction, in which Magnevist® is eliminated only very slowly and can beremoved partially from the organism only with the help of a dialyzer.

Therefore, there is a need for NMR contrast media which show apharmacokinetic behavior other than that of Magnevist®.

This invention makes available such compounds and agents as well as toprovide a process for their production.

It has been found that the compounds according to the inventionsurprisingly show the desired properties: both renal elimination andexcretion with the feces after parenteral administration. But,surprisingly, the elimination through the gallbladder is not the onlymethod of extrarenal elimination: in the case of NMR tests in rats, acontrast enhancement of the gastrointestinal tract was also unexpectedlyobserved after intravenous administration of the compounds according tothe invention, e.g., these compounds are suitable both for theorgan-specific NMR diagnosis of the hepatobiliary system and thestomach. The kidneys as well as implanted tumors are optionallycontrasted.

Surprisingly, the complex compounds according to the invention are alsoresorbed after oral administration and then are eliminated through thehepatobiliary system, i.e., they are suitable as oral liver contrastmedia.

Such a phenomenon was not previously described of any contrast mediumfor nuclear spin tomography. The elimination (secretion) through thestomach has the advantage that a differentiation of abdominal structures(e.g., pancreas) from the gastrointestinal tract is made possible withsimultaneous contrast enhancement of pathological processes (tumors,inflammations). A representation of the renal system, the liver and thegallbladder and biliary tract as well as the lymph nodes can, moreover,also be achieved. Besides the improved representation of ulcers andstomach cancers, a study of the gastric secretion can also be performedwith the help of the imaging processes.

By the use of the above-mentioned compounds--in addition to thediagnosis of the hepatobiliary system--patients suffering from bothrenal insufficiencies and gastrointestinal diseases (at least 10% of thepopulation in the western industrialized countries) thus can be helped.Most of these patients, as well as a large number of patients suspectedof having such a disease, have to undergo diagnostic tests. Two suitablemethods in this respect for gastrointestinal diseases above all are nowcustomary: endoscopy and X-ray diagnosis with the help of bariumcontrast media.

These tests exhibit different drawbacks: they are affected by the riskof the radiation exposure, trauma-causing, connected withinconveniences, occasionally even with risks for the patients, and cantherefore cause psychological stress. They mostly have to be performedrepeatedly, are relatively expensive to perform, require the activecooperation of the patient (e.g., taking a certain posture), and oftencannot be used with infirm or with high-risk patients.

The object, to make available new diagnostic methods to recognize andlocalize gastrointestinal diseases which do not have these drawbacks, istherefore also achieved by the use of the above-mentioned complexcompounds and agents.

Also, without specific measures, their pharmacokinetics makes possiblethe improvement of the diagnosis of numerous diseases. The complexes areunchanged for the most part and are again eliminated quickly, so that noharmful effects are observed especially also in the case of the use ofrelatively toxic metal ions even in the case of high dosages.

The practical use of the new complexes is also facilitated by theiradvantageous chemical stability.

The compounds according to the invention are characterized by generalformula I: ##STR2## in which Z¹ and Z² each stand for a hydrogen atom orthe radical

--(CH₂)_(m) --(C₆ H₄)_(q) --(O)_(k) --(CH₂)_(n) --(C₆ H₄)_(l) --(O)_(r)--R,

in which

m and n independently mean numbers 0-20,

k, l, q and r independently mean numbers 0 and 1 and

R means a hydrogen atom, an optionally OR¹ -substituted C₁ -C₆ alkylradical or a CH₂ COOR¹ group with R¹ meaning a hydrogen atom, a C₁ -C₆alkyl radical or a benzyl group,

R² stands for a saturated, unsaturated, straight-chain or branched-chainor cyclic non-aromatic hydrocarbyl group with up to 20 C-atoms, an arylgroup (e.g., of up to 10 C-atoms) or aralkyl group (e.g., of up to 16C-atoms), all substituted by a carboxyl group or a sulfone group, eachoptionally esterified with a C₁ -C₆ alkyl radical or benzyl radical,

R³ stands for a hydrogen atom or for a saturated, unsaturated,straight-chain or branched-chain or cyclic non-aromatic hydrocarbyl,e.g., alkyl group with up to 20 C-atoms, an aryl group (e.g., of up to10 C-atoms) or aralkyl group (e.g., of up to 16 C-atoms), all optionallysubstituted by a carboxyl group or sulfone group, each optionallyesterified with a C₁ -C₆ alkyl radical or benzyl radical,

X stands for a hydrogen atom and/or a metal ion equivalent of an elementof atomic numbers 21-29, 31, 32, 37-40, 42-44, 49 or 57-83, providedthat at least one of substituents Z¹ and Z² stands for a hydrogen atom,that--if n and 1 each stand for the number 0-k and r are not the number1 at the same time and that the radical of the acid groups is optionallypresent as an ester or amide, as well as their salts with inorganicand/or organic bases, amino acids or amino acid amides.

Compounds of general formula I with X meaning hydrogen are designated ascomplexing agents and, with at least two of substituents X meaning ametal ion equivalent, they are designated as metal complexes.

The element of the above-mentioned atomic number, which forms thecentral ion of the physiologically compatible complex salt can, ofcourse, also be radioactive for the desired purpose of the diagnosticagent according to the invention.

Thus, if the agent according to the invention is intended for use in NMRdiagnosis, the central ion of the complex salt has to be paramagnetic.These are in particular the divalent and trivalent ions of the elementsof atomic numbers 21-29, 42, 44 and 58-70. Suitable ions are, forexample, the chromium(III), manganese(II), iron(II), cobalt(II),nickel(II), copper(II), praseodymium(III), neodymium(III),samarium(III), and ytterbium(III) ion. Because of their very strongmagnetic moment, the gadolinium(III), terbium(III), dysprosium(III),holmium(III), erbium(III), and iron(III) ions are especially preferred.

The central ion has to be radioactive for the use of the agentsaccording to the invention in nuclear medicine. For example,radioisotopes of the elements copper, cobalt, gallium, germanium,yttrium, strontium, technetium, indium, ytterbium, gadolinium, samariumand iridium are suitable.

Thus, if the agent according to the invention is intended for use in theX-ray diagnosis, the central ion has to be derived from an element of ahigher atomic number to achieve a sufficient absorption of the X-rays.It has been found that, for this purpose, diagnostic agents, whichcontain a physiologically compatible complex salt with central ions fromelements of atomic numbers between 21-29, 42, 44, 57-83, are suitable;these are, for example, the lanthanum(III) ion and the above-mentionedions of the lanthanide group.

The numbers standing for m and n are preferably 0 to 5.

As the hydrocarbon portions of R, R¹ and R², straight-chain or branchedhydrocarbons, especially alkyl groups, all with up to 6 carbon atoms,preferably up to 4 carbon atoms, which are optionally substituted in thecase of R by one or more, preferably 1 to 3, hydroxy groups or C₁ -C₆alkoxy groups, preferably C₁ -C₄ alkoxy groups, are suitable.

As optionally substituted alkyl groups, for example, there can bementioned the methyl, hydroxymethyl, ethyl, 2-hydroxyethyl,2-hydroxy-1-(hydroxymethyl)-ethyl, 1-(hydroxymethyl)-ethyl, propyl,isopropyl, 2- and 3-hydroxypropyl, 2,3-dihydroxypropyl, n-, sec-, andtert-butyl, 2-, 3-, and 4-hydroxybutyl, 2- and 3-hydroxyisobutyl,pentyl, 2-, 3-, and 4-hydroxy-2-methylbutyl, 2,3,4-trihydroxybutyl,1,2,4-trihydroxybutyl, cyclopentyl, cyclohexyl,2,3,4,5,6-pentahydroxyhexyl group as well as--in the case of thehydroxyalkyl groups--their C₁ -C₆ alkyl derivatives, preferably C₁ -C₄alkyl derivatives, i.e., OH groups where the H-atom is replaced by saidgroups.

As preferred aryl group and aralkyl groups R² and R³, there can bementioned the phenyl, benzyl, and isopropylphenyl radicals.

Preferred substituents Z¹ or Z² are the --CH₂ --C₆ H₄ --OH, --CH₂ --C₆H₄ --OCH₃, --CH₂ C₆ H₅, --CH₂ --C₆ H₄ --O--CH₂ --C₆ H₄ --OCH₃, --CH₂--O--CH₂ --C₆ H₅, --CH₂ --C₆ H₄ --O--CH₂ --COOH, --CH₂ --C₆ H₄ --OC₂ H₅,--CH₂ --C₆ H₄ --OC₄ H₉, --CH₂ --C₆ H₄ --O--CH₂ --C₆ H₅ radical.

Above and below, the substituents can be placed on any C-atom of themain group to which they are attached. Typically, there are 1-6 OR'substituents, preferably up to one per C-atom.

Saturated, unsaturated, straight-chain, branched-chain or cyclichydrocarbyl, e.g., alkyl groups, with up to 20 C-atoms, preferably with5 to 18 C-atoms, aryl groups and aralkyl groups are suitable as radicalsR² and R³, in each case substituted (R²) or optionally substituted (R³)by a carboxyl group or sulfone group, optionally esterified with a C₁-C₆ alkyl radical, preferably C₁ -C₄ alkyl, or benzyl radical.

For example, there can be mentioned the methyl, ethyl, propyl,isopropyl, butyl, pentyl, hexyl, phenyl, benzyl, 4-carboxy-phenylene,1-cyclohexyl-1-carboxylic acid, 1-cyclopentyl-1-carboxylic acid,2-carboxyphenylene, 11-carboxy-1-undecyl, 10-carboxy-1-decyl,7-carboxy-1-heptyl, 6-carboxy-1-hexyl, 5-carboxy-1-pentyl,4-carboxy-benzyl, 4-carboxy-1-cyclohexylmethyl,4-carboxymethyl-phenylene, 4-(1,1-dimethylcarboxymethylene)-phenylene,4-sulfophenylene, 10-sulfo-1-decyl, 8-sulfo-1-octyl,17-carboxy-7-heptadecyl, 7-carboxy-2-heptyl,1-carboxy-4-phenyl-2-propyl, 2-carboxyethyl, 4-carboxy-4-but-1-enylradicals.

The residual acidic hydrogen atoms, i.e., those which have not beensubstituted by the central ion, can optionally be replaced completely orpartially by cations of inorganic and/or organic bases or amino acids.The corresponding acid groups can also be converted completely orpartially to esters or amides.

Suitable inorganic cations are, for example, the lithium ion, thepotassium ion, the calcium ion, the magnesium ion and in particular thesodium ion. Suitable cations of organic bases are, among others, thoseof primary, secondary or tertiary amines, such as, for example,ethanolamine, diethanolamine, morpholine, glucamine,N,N-dimethylglucamine and in particular N-methylglucamine. Suitablecations of amino acids are, for example, those of lysine, arginine andornithine as well as the amides of the otherwise acid or neutral aminoacids.

Suitable esters are preferably those with a C₁ -C₆ alkyl radical: forexample, there can be mentioned the methyl, ethyl, and tert-butyl,benzyl, and 4-methoxybenzyl radical.

Thus, if the carboxylic acid groups are to be present at least partiallyas amides, saturated, unsaturated, straight-chain or branched-chain orcyclic hydrocarbons with up to 5 C-atoms are suitable as radicals, whichare optionally substituted by 1 to 3 hydroxy groups or C₁ -C₄ alkoxygroups. For example, there can be mentioned the methyl, ethyl,2-hydroxyethyl, 2-hydroxy-1-(hydroxymethyl)-ethyl,1-(hydroxymethyl)-ethyl, propyl, isopropenyl, 2-hydroxypropyl,3-hydroxypropyl, 2,3-dihydroxypropyl, butyl, isobutyl, isobutenyl,2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl,2,3,4-hydroxy-2-methylbutyl, 2- and 3-hydroxyisobutyl,2,3,4-trihydroxybutyl, 1,2,4-trihydroxybutyl, pentyl, cyclopentyl, and2-methoxyethyl group. The amide radical can also be a heterocyclic 5- or6-ring formed with the inclusion of the amide-nitrogen. By way ofexample, there can be mentioned: the pyrrolidinyl, piperidyl,pyrazolidinyl, pyrrolinyl, pyrazolinyl, piperazinyl, morpholinyl,imidazolidinyl, oxazolidinyl, thiazolidinyl ring.

The compounds according to the invention exhibit the initially describeddesired properties. Moreover, the compatibility of the monoamidesaccording to the invention is surprisingly increased in comparison withthe corresponding bisamides. Thus, for example, the LD₅₀ value (rat) ofthe compound of Example 1b) (preferred for use in imaging thehepatobiliary system, e.g., the liner) is higher by the factor 3 thanthe corresponding value of the previously known (DE-OS 34 01 052.1,Example 2) bisamide. However, based on the prior art, a falling off ofthe LD₅₀ value was to be expected: thus, for example, the LD₅₀ (mouse)value or LD₅₀ (rat) value of the bisamide gadolinium complex of N⁶-carboxymethyl-N³,N⁹-bis(2,3-dihydroxypropyl-N-methyl-carbamoylmethyl)-3,6,9-triazaundecanedioicacid European Patent Publication No. 0 130 934, Example 6a)! drops by 50or 30% in the case of the corresponding monoamide (formula I, Z¹ =Z² =M,R² =--CH₂ CH(OH)CH₂ OH, R³ =CH₃).

The introduction of amide groups for the production of complexingagents, i.e. of compounds of general formula I with X meaning hydrogen,takes place by partial conversion of activated carboxyl groups intoamide groups of--corresponding to the desired end product--suitablepentacarboxylic acids each. For this process, all synthesispossibilities known to one skilled in the art are suitable.

An example for this purpose is the reaction of the anhydrides or estersof general formulas II and III ##STR3## in which Z¹ and Z² have theabove-indicated meanings,

R⁴ stands for the radical of an activated carbonyl group or for OR⁵ and

R⁵ represents a hydrogen atom or a C₁ -C₆ alkyl radical, with aminoacids of general formula IV ##STR4## in which R² and R³ have theabove-mentioned meanings.

As examples for an activated carbonyl group, there are cited mixedanhydride (with, e.g., chloroformic acid ester) and the addition producton carbodiimides, e.g., dicyclohexylcarbodiimide (DCC).

As suitable amino acids, for example, there can be mentioned:

4-aminobenzoic acid, 1-aminocyclohexane-1-carboxylic acid,1-aminocyclopentane-1-carboxylic acid, 2-aminobenzoic acid,12-aminododecanoic acid, 11-aminoundecanoic acid, 8-aminooctanoic acid,7-aminoheptanoic acid, 6-aminohexanoic acid, 4-aminomethylbenzoic acid,trans-4-(aminomethyl)-cyclohexanecarboxylic acid, p-aminophenylaceticacid, alpha,alpha-dimethyl-p-aminophenylacetic acid, sulfanilic acid,10-aminodecane-1-sulfonic acid, 8-aminooctane-1-sulfonic acid,12-aminooctadecanoic acid, 2-aminooctanoic acid, 2-amino-4-phenylbutyricacid, iminodiethanoic acid, N-methylaminobenzene-4-sulfonic acid,12-methylaminododecanoic acid, 2-amino-4-pentenoic acid.

The saponification of optionally still present ester groups takes placeaccording to the processes known to one skilled in the art, for exampleby alkaline hydrolysis.

The production of the monoanhydrides of general formula III with R⁵ =C₁-C₆ alkyl radical is to be described by the example of the monoanhydrideof diethylenetriaminepentaacetic acid ethyl ester, starting from themonoethyl ester of DTPA (J. Pharm. Sci. 68, 1979, 194):

The production of the monoanhydrides of general formula III with R⁵ =Htakes place according to the methods known to one skilled in the art(cf. also the experimental part) by partial saponification of thecorresponding bisanhydrides, and the monoanhydrides resulting in thiscase do not have to be isolated.

N³ -(2,6-Dioxomorpholinoethyl)-N⁶-(ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid

A suspension of 21.1 g (50 mmol) of N³,N⁶ -bis-(carboxymethyl)-N⁹-(ethoxy-carbonylmethyl)-3,6,9-triazaundecanedioic acid in 250 ml ofacetic anhydride is allowed to stir for three days at room temperatureafter the addition of 42.2 ml of pyridine. Then, the precipitate issuctioned off, washed three times with 50 ml of acetic anhydride eachand then stirred for several hours with absolute diethyl ether. Aftersuctioning off, washing with absolute diethyl ether and drying in avacuum at 40° C., 18.0 g (=89% of theory) of a white powder with amelting point of 195°-196° C. is obtained.

Analysis (relative to the anhydrous substance): Calculated: C 47.64 H6.25 N 10.42; Found: C 47.54 H 6.30 N 10.22

The reaction of the acid anhydrides in the amides is performed in theliquid phase. Suitable reaction media are, for example, water, dipolaraprotic solvents such as acetonitrile, N-methylpyrrolidone,dimethylformamide, dimethylacetamide and the like or mixtures of thesame. The reaction temperatures are between about 0° C.-100° C., andtemperatures of 20° C.-80° C. are preferred. The reaction times arebetween 0.5 hours and 2 days, preferably between 1 hour and 36 hours.

The production of the esters of general formula II takes place in aknown way, e.g., according to the process described in R. A. Guilmetteet al., J. Pharm. Sci. 68, 194 (1979).

The aminolysis of the esters takes place in the liquid phase, e.g., in asuitable, higher-boiling solvent, such as dimethylformamide,dimethylacetamide or dimethyl sulfoxide. The reaction temperatures areat about 20° C.-200° C., and temperatures of 100° C.-180° C. arepreferred. The reaction times are between 2 hours and 2 days, andreaction times between 4 hours and 36 hours are preferred.

Further, all methods known to one skilled in the art for conversion ofcarboxyl groups to amide groups for synthesis of the complexing agentsof general formula I according to the invention, can be used, thus,e.g., the method according to Krejcarek and Tucker, Biochem. Biophys.Res. Commun. 77, 581 (1977) on mixed anhydrides. Other methods toconvert activated carbonyl groups are described, e.g., in J. Nucl. Med.24, 1158 (1983), Bioconjugate Chem. 1, 65 (1990), Org. Prep. Proc. Int.7, 215 (1975), Adv. Org. Chem. Part B, 472 and Fieser, Reagents forOrganic Syntheses 10, 142 (carbodiimide).

The production of the compounds needed as initial substances for theC-substituted (i.e. one of substituents Z¹ and Z² is not hydrogen)anhydrides or esters of general formulas II and III takes place in that,in a way known in the art, compounds of general formula V ##STR5## inwhich R⁶ stands for an acid protecting group,

Z³ and Z⁴ each stand for a hydrogen atom or the radical --(CH₂)_(m)--(C₆ H₄)_(q) --OH, provided that one of substituents Z³ and Z⁴ standsfor a hydrogen atom and the other for the indicated radical, areconverted to a compound with the radical indicated for Z¹ and Z² andacid protecting groups R⁶ are cleaved.

As acid protecting groups R⁶, lower alkyl, aryl, and aralkyl groups aresuitable, for example, the methyl, ethyl, propyl, n-butyl, t-butyl,phenyl, benzyl, diphenylmethyl, triphenylmethyl,bis(p-nitrophenyl)-methyl group as well as trialkylsilyl groups.

The cleavage of protecting groups R⁶ takes place according to theprocesses known to one skilled in the art e.g., E. Wuensch, Methoden derOrg. Chemie Methods of Org. Chemistry! (Houben-Weyl), Vol. XV/1, 4thedition 1974, p. 315 ff!, for example, by hydrolysis, hydrogenolysis oralkaline saponification of the esters with alkali in aqueous alcoholicsolution at temperatures of 0° to 50° C. Organic or inorganic acids areused for cleavage of the t-butylesters especially advantageous for thesereactions: the ester compound dissolved in a suitable anhydrous organicsolvent, but preferably the pulverized dry substance, is mixed eitherwith hydrogen halide solution in glacial acetic acid, withtrifluoroacetic acid or also boron trifluoride diethyl etherate inglacial acetic acid and cleaved at temperatures of -10° C. to 60° C.,preferably at room temperature.

The compounds of general formula V being used as feedstocks for theproduction of the complex compounds according to the invention are known(DOS 3 710 730 and the literature cited there) or can be synthesizedanalogously to the production instructions described there.

A number of methods known to one skilled in the art from literature areavailable for the reaction of the known aliphatic or aromatic hydroxycompounds to the corresponding aryl-alkyl ethers or dialkyl ethers(e.g., J. March, Advanced Organic Chemistry, third edition 1985, p. 342ff).

For this purpose, the compounds of formula V, in which R⁶ stands for analkali-stable acid protecting group, are dissolved in a polar aproticsolvent, such as, e.g., tetrahydrofuran, dimethoxyethane or dimethylsulfoxide and mixed with a base, such as, e.g., sodium hydride, sodiumhydroxide or alkali carbonates or alkaline-earth carbonates, attemperatures between -30° C. and the boiling point of the respectivesolvent, but preferably between 0° C. and 60° C.

For this purpose, a compound of general formula VI

    Y--(CH.sub.2).sub.n --(C.sub.6 H.sub.4).sub.l --(O).sub.r --R(VI)

is added, in which Y stands for a nucleofuge, such as, e.g., Cl, Br, I,CH₃ --C₆ H₄ SO₃ or CF₃ SO₃ and the usual indices have the same meaningas in general formula I.

The reaction times are 30 minutes to 8 hours depending on sterichindrance of the radicals involved.

As an alternative to the above-described reaction conditions, botharylalkyl ether and dialkyl ether can be produced very advantageously byphase transfer catalysis (Starks and Liotta, Phase Transfer Catalysis,Academic Press, N.Y. 1978, pp. 128-138).

For this purpose, the reaction is performed in a two-phase mixture ofaqueous base, preferably 30% sodium hydroxide solution, and an organicaprotic solvent which is water-immiscible. As phase transfer catalysts,the compounds known to one skilled in the art are suitable, butpreferably tetraalkylammonium or tetraalkylphosphonium salts.

If compounds of general formula I with k, n, l and r=Q and R meaning ahydrogen atom are to be synthesized, it is possible, starting from thecorresponding unsubstituted amino acids (e.g., phenylalanine), toperform the synthesis analogously to methods known in the literature.

But if a number of analogous compounds are synthesized, therepresentation of the phenol derivatives described in DOS 3 710 730 andthe reductive removal of the phenol function according to the literatureprocesses known to one skilled in the art are advisable. Above all, thereduction of aryldiethyl phosphates with titanium can be mentioned whichcan be very advantageously performed also in the presence of estergroups S. C. Welch et al., J. Org. Chem. 43, 4797-99 (1978) and theliterature cited there!. In this case, the corresponding aryldiethylphosphate is first formed from the phenolic feedstock by reaction withphosphoric acid diethyl ester chloride in 70 to 100% yield, preferablyby use of sodium hydride as a base in a polar aprotic solvent. Then thereduction with freshly produced titanium metal is performed. Preferably,anhydrous titanium(III) chloride is reduced by magnesium or potassium inanhydrous tetrahydrofuran under inert gas for the production of highlyactive titanium.

The above-described diethyl phosphate is added to such a mixture andrefluxed for 2 to 24 hours, preferably 6 to 16 hours. After completionof the reaction, it is optionally chromatographically worked up. Thepalladium-catalyzed reduction of the corresponding aryl triflates isalso usable according to S. Cacchi et al., Tetr. Lett. 27, 5541-44(1986).

The compounds of general formula I, thus obtained finally, with Xmeaning a hydrogen atom, represent complexing agents. They can beisolated and purified or converted without isolation to metal complexesof general formula I with at least two of substituents X meaning a metalion equivalent.

The production of the metal complexes according to the invention takesplace in the way disclosed in German laid-open specification 34 01 052,by the metal oxide or a metal salt (for example, the nitrate, acetate,carbonate, chloride or sulfate) of the element of atomic numbers 21-29,42, 44, 57-83 being dissolved or suspended in water and/or a loweralcohol (such as methanol, ethanol or isopropanol) and reacted with thesolution or suspension of the equivalent amount of the complexingligands and then, if desired, present acidic hydrogen atoms beingsubstituted by cations of inorganic and/or organic bases or amino acids.

The neutralization of possibly still present free acid groups takesplace with the help of inorganic bases (for example, hydroxides,carbonates or bicarbonates) of, for example, sodium, potassium, lithium,magnesium or calcium and/or organic bases, such as, among others,primary, secondary and tertiary amines, such as, for example,ethanolamine, morpholine, glucamine, N-methylglucamine andN,N-dimethylglucamine, as well as basic amino acids, such as, forexample, lysine, arginine and ornithine or of amides of originallyneutral or acid amino acids.

For production of neutral complex compounds, for example, of the acidcomplex salts in aqueous solution or suspension as much as the desiredbases can be added, so that the neutral point is reached. The solutionobtained can then be evaporated to dryness in a vacuum. It is oftenadvantageous to precipitate the formed neutral salts by addingwater-miscible solvents, such as, for example, lower alcohols (methanol,ethanol, isopropanol and others), lower ketones (acetone and others),polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane and others)and thus easily to obtain crystallizates that can be easily isolated andpurified. It has proven especially advantageous to add the desired basealready during the complexing of the reaction mixture and thus to save aprocess step.

If the acid complex compounds contain several free acidic groups, it isoften advisable to produce neutral mixed salts which contain bothinorganic and organic cations as counterions.

This can happen, for example, by the complexing ligands in aqueoussuspension or solution being reacted with the oxide or salt of theelement providing the central ion and half of the amount needed forneutralization of an organic base, the formed complex salt beingisolated, optionally purified and then, for complete neutralization,being mixed with the necessary amount of an inorganic base. The sequenceof addition of the bases can also be reversed.

Another possibility to achieve neutral complex compounds consists inconverting the remaining acid groups in the complex completely orpartially to, for example, esters or amides. This can happen by laterreaction on the finished complex (e.g., by exhaustive reaction of thefree carboxy groups with dimethyl sulfate).

The production of the pharmaceutical agents according to the inventionalso takes place in a way known in the art, by the complex compoundsaccording to the invention--optionally by adding the additives usual ingalenicals--being suspended or dissolved in an aqueous medium and thenthe suspension or solution optionally being sterilized. Suitableadditives are, for example, physiologically harmless buffers (such as,for example, tromethamine), additives of complexing agents (such as, forexample, diethylenetriaminepentaacetic acid) or--ifnecessary--electrolytes, such as, for example, sodium chloride or--ifnecessary--antioxidants, such as, for example, ascorbic acid.

If suspensions or solutions of the agents according to the invention inwater or physiological salt solution are desired for the enteraladministration or other purposes, they are mixed with one or moreauxiliary agent(s) (for example, methyl cellulose, lactose, mannitol)and/or surfactant(s) (for example, lecithins, Tween®, Myrj° and/oraromatic substance(s) for taste correction (for example, ethereal oils)which are usual in galenicals.

On principle, it is also possible to produce the pharmaceutical agentsaccording to the invention even without isolating the complex salts. Ineach case, special care then has to be used to carry out the chelateformation so that the salts and salt solutions according to theinvention are practically free of noncomplexed, toxically acting metalions.

This can be assured, for example, with the help of color indicators suchas xylenol orange by control filtrations during the production process.The invention therefore also relates to processes for the production ofcomplex compounds and their salts. A purification of the isolatedcomplex salt remains as a final safety measure.

The pharmaceutical agents according to the invention preferably contain0.1 micromol-1 mol/l of complex salt and are generally dosed in amountsof 0.1 micromol-5 mmol/kg. They are intended for enteral and parenteraladministration. The complex compounds according to the invention areused

1. for the NMR and X-ray diagnosis in the form of their complexes withthe ions of the elements with atomic numbers 21-29, 42, 44 and 57-83;

2. for the radiodiagnosis and the radiotherapy in the form of theircomplexes with the radioisotopes of the elements with atomic numbers 21,27, 29, 31, 32, 37-40, 43, 49, 62-64, 70, 75 and 77.

The agents according to the invention meet the varied requirements forsuitability as contrast media for the nuclear spin tomography. Thus,they are excellently suited for this purpose, after oral or parenteraladministration, to improve the image, obtained with the help of thenuclear spin tomography, in its expressiveness by increasing the signalintensity. Further, they show the high effectiveness which is necessaryto load the body with the smallest possible amounts of foreignsubstances, and the good compatibility which is necessary to maintainthe noninvasive nature of the tests.

The good water solubility and low osmolality of the agents according tothe invention make it possible to produce highly concentrated solutions,thus to keep the volume load of the circulatory system withinjustifiable limits and to offset the dilution by the body fluid, i.e.,NMR diagnostic agents have to be 100 to 1000 times more water-solublethan for the NMR spectroscopy. Further, the agents according to theinvention exhibit not only a high stability in vitro but also asurprisingly high stability in vivo, so that a release or an exchange ofthe ions--toxic in themselves--noncovalently bound in the complexestakes place only extremely slowly within the time in which the newcontrast media are again completely excreted.

In general, the agents according to the invention for use as NMRdiagnostic agents are dosed in amounts of 0.0001-5 mmol/kg of bodyweight, preferably 0.005-0.5 mmol/kg of body weight of the complexaccording to the invention. Aqueous formulations of the concentration of50 micromol/l to 2 mol/l, preferably 100 mmol/l to 1 mol/l, are used inan intravenous injection. A rectal as well as an oral use is preferablyperformed with solutions of the concentration 0.1 mmol to 100 mmol/l oras solid in the corresponding concentration range. The volumesadministered are between 5 ml and 2 l depending on the diagnosticformulation of the problem. Details of the use are discussed, forexample, in H. J. Weinmann et al., Am. J. of Roentgenology 142, 619(1984).

Especially low dosages (less than 1 mg/kg of body weight) oforgan-specific NMR diagnostic agents can be used, for example, fordetection of tumors and myocardial infarctions.

Further, the complex compounds according to the invention can be usedadvantageously as susceptibility reagents and as shift reagents for thein vivo NMR spectroscopy.

The agents according to the invention are suitable also asradiodiagnostic agents because of their advantageous radioactiveproperties and the good stability of the complex compounds contained inthem. Details of their use and dosage are described, e.g., in"Radiotracers for Medical Applications," CRC Press, Boca Raton, Fla.

Another imaging method with radioisotopes is the positron emissiontomography, which uses positron-emitting isotopes, such as, e.g. ⁴³ Sc,⁴⁴ Sc, ⁵² Fe, ⁵⁵ Co and ⁶⁸ Ga (Heiss, W. D.; Phelps, M. E.; PositronEmission Tomography of Brain, Springer Verlag Berlin, Heidelberg, NewYork 1983).

The compounds according to the invention can also be used inradio-immunotherapy or radiation therapy. These are distinguished fromthe corresponding diagnostic agents only by the amount and type of theisotope used. In this case, the purpose is the destruction of the tumorcells by high-energy shortwave radiation with a smallest possible rangeof action. Suitable beta-emitting ions are, for example, ⁴⁶ Sc, ⁴⁷ Sc,⁴⁸ Sc, ⁷² Ga, ⁷³ Ga and ⁹⁰ Y. Suitable alpha-emitting ions exhibitingsmall half-lives are, for example, ²¹¹ Bi, ²¹² Bi, ²¹³ Bi and ²¹⁴ Bi,and ²¹² Bi is preferred. A suitable photon- and electron-emitting ion is¹⁵⁸ Gd, which can be obtained from ¹⁵⁷ Gd by neutron capture.

If the agent according to the invention is intended for use in thevariant of the radiation therapy proposed by R. L. Mills et al. NatureVol. 336, (1988), p. 787!, the central ion has to be derived from aMoessbauer isotope, such as, for example, ⁵⁷ Fe or ¹⁵¹ Eu.

In the in vivo administration of the therapeutic agents according to theinvention, the latter can be administered together with a suitablevehicle, such as, for example, serum or physiological common saltsolution and/or together with another protein, such as, for example,human serum albumin. The dosage in this case is dependent on the type ofcellular impairment, the metal ion used and the type of method, e.g.,brachytherapy.

The therapeutic agents according to the invention are administeredparenterally, preferably i.v.

Details of the use of radiotherapeutic agents are discussed, e.g., in R.W. Kozak et al. TIBTEC, October 1986, 262.

The agents according to the invention are excellently suited as X-raycontrast media, and it is to be emphasized especially that with them, nosigns of the anaphylactic-type reactions, known from theiodine-containing contrast media, can be discerned inbiochemical-pharmacological tests. They are especially valuable becauseof the advantageous absorption properties in the areas of higher tubevoltages for digital substraction techniques.

In general, the agents according to the invention for use as X-raycontrast media are dosed analogously to, for example,meglumine-diatrizoate in amounts of 0.1-5 mmol/kg, preferably 0.25-1mmol/kg.

Details of the use of X-ray contrast media are discussed, for example,in Barke, Roentgenkontrastmittel X-Ray Contrast Media!, G. Thieme,Leipzig (1970) and P. Thurn, E. Buecheler--"Einfuehrung in dieRoentgendiagnostik" Introduction to the X-Ray Diagnosis!, G. Thieme,Stuttgart, N.Y. (1977).

Altogether, it has been possible to synthesize new complexing agents,metal complexes and metal complex salts, which open up new possibilitiesin diagnostic and therapeutic medicine. Above all, the development ofnovel imaging processes in medical diagnosis makes this developmentappear desirable.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius and unless otherwise indicated, allparts and percentages are by weight.

The entire disclosure of all applications, patents and publications,cited above and below, and of corresponding German application P 40 11684.0, are hereby incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an MRI image of a test animal (rat) made without theadministration of contrast media.

FIG. 2 is an MRI image of a test animal (rat) taken 60 minutes after theadministration of cantrast medium (Example 1b).

FIG. 3 is an MRI image of a test animal (rat) taken 45 minutes after theadministration of contrast medium (Example 1b).

FIG. 4 is an MRI image of a test animal (rat) taken 180 minutes afterthe administration of contrast medium (Example 1b).

EXAMPLES Example 1

a)3,6-Bis(carboxymethyl)-9-(10-carboxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid

15.33 g (38 mmol) of N³ -(2,6-dioxomorpholinoethyl)-N⁶-(ethoxy-carbonylmethyl)-3,6-diazaoctanedioic acid (Example 13a of EP0331 616) is suspended in dimethylformamide (DMF) and mixed in an icebath with 21.07 ml (152 mmol) of triethylamine and 7.65 g (38 mmol) of11-aminoundecanoic acid. The temperature is allowed to increase to roomtemperature and the reaction solution is stirred overnight. Aftercompletion of the reaction, the possibly still slightly cloudy solutionis filtered and the filtrate is concentrated by evaporation in a vacuum.The residue is absorptively precipitated with ether and thenrecrystallized from water (17.8 g). The ethyl ester is dissolved in 2 NNaOH and is adjusted to pH 7 after 3 hours by adding Amberlite® IR 120(H⁺). The ion exchange material is suctioned off, the filtrate isfreeze-dried (20.1 g) and then added to H₂ O/methanol (2:1) on 100 ml ofAmberlite° IR 120 (H⁺) and the acid eluate is concentrated byevaporation and recrystallized from water.

Yield: 13.0 g (59.3%); Melting point: 168° C.; Analysis (relative to theanhydrous substance): Calculated: C 52.07 H 7.69 N 9.72; C 51.98 H 7.61N 9.75

b) Gadolinium complex of3,6-bis(carboxymethyl)-9-(10-carboxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid

8.65 g (15 mmol) of the complexing agent acid described in Example 1a issuspended in 200 ml of H₂ O and mixed with 2.72 g (7.5 mmol) of Gd₂ O₃and held at 90° C. for 60 minutes on the water bath. The solution isfiltered by a membrane filter, frozen and freeze-dried.

Yield: 11.9 g (quantitative); H₂ O content: 9.2% (Karl-Fischer);Analysis (relative to the anhydrous substance): Calculated: C 41.08 H5.65 Gd 21.52 N 7.67; C 41.12 H 5.69 Gd 21.37 N 7.59

c) Europium complex of3,6-bis(carboxymethyl)-9-(10)-carboxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid

Analogously, the title compound is obtained as a white powder with anuncharacteristic decomposition point from the complexing agent acid,described in Example 1a, with europium oxide, Eu₂ O₃, in quantitativeyield.

Analysis (relative to the anhydrous substance): Calculated: C 40.52 H5.58 N 7.56 Eu 22.58; C 40.60 H 5.65 N 7.63 Eu 22.51

d) Iron(III) complex of3,6-bis-(carboxymethyl)-9-(10-carboxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid

Analogously, the title compound is obtained as a brown powder with anuncharacteristic decomposition point from the complexing agent acid,described in Example 1a, with iron(III) oxide, Fe₂ O₃, in quantitativeyield.

Analysis (relative to the anhydrous substance): Calculated: C 63.19 H9.33 N 11.79 Fe 11.75; C 63.04 H 9.42 N 11.68 Fe 11.79

e) Bismuth(III) complex of3,6-bis-(carboxymethyl)-9-(10-carboxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid

Analogously, the title compound is obtained as a brown power with anuncharacteristic decomposition point from the complexing agent acid,described in Example 1a, with bismuth(III)oxide, Bi₂ O₃, in quantitativeyield.

Analysis (relative to the anhydrous substance): Calculated: C 47.79 H7.06 N 8.92 Bi 33.26; C 47.83 H 7.11 B 8.88 Bi 33.10

Example 2

a)6-Carboxymethyl-9-(4-carboxymethyl-phenyl)-carbamoylmethyl-3-ethoxycarbonylmethyl-3,6,9-triazaundecanedioicacid

3.02 g (20 mmol) of p-aminophenylacetic acid is added to a suspension of8.07 g (20 mmol) of N³ -(2,6-dioxomorpholinoethyl)-N⁶ -(ethoxy-carbonylmethyl)-3,6-diazaoctanedioic acid in 100 ml ofdimethylformamide at 45° C. with stirring, then stirred overnight atroom temperature, the solvent is largely evaporated in a vacuum and theresidue is stirred with 100 ml of methyl tert-butyl ether, suctioned offand the residue is dried in a vacuum at 50° C. The crude product thusobtained is suspended with 10 ml of water. It is mixed with 11 N sodiumhydroxide solution up to pH 7, and the substance goes into solution. 10g of silica gel is added to the solution, the suspension is concentratedby evaporation in a rotary evaporator and the residue is added to acolumn with 700 g of silica gel, which was taken up with a mixture ofchloroform-methanol-glacial acetic acid-water (18-10-4-4). It is elutedwith the same solvent and, after concentration by evaporation of theeluate, 8.3 g of oily product is isolated that is dissolved in 75 mlwater for removal of sodium ions and is added to a column of 75 ml ofcation exchanger IR 120. The column is eluted with 150 ml of water andthe aqueous solution is concentrated by evaporation in a vacuum. Theresidue is stirred with 50 ml of diethyl ether, suctioned off, dried ina vacuum, and 6.2 g of the title compound is obtained as a white powder.

Analysis (relative to the anhydrous substance): Calculated: C 51.98 H6.18 N 10.10; C 51.81 H 6.33 N 10.18

b)3,6-Bis(carboxymethyl)-9-(4-carboxymethylphenyl)-carbamoylmethyl-3,6,9-triazaundecanedioicacid

90 ml of 1N sodium hydroxide solution is added to a solution of 5 g ofthe ester, produced according to part a), in 20 ml of water, allowed tostand for 3 hours at room temperature and about 200 ml of cationexchanger IR 120 is added to the solution with stirring, the solutionthen has a pH of 2.3. After filtration, the solution is freeze-dried.3.90 g of the title compound is obtained as a white powder.

Analysis (relative to the anhydrous substance): Calculated: C 50.19 H5.74 N 10.64; C 50.03 H 5.71 N 10.72

c) Gadolinium complex of3,6-bis(carboxymethyl)-9-(4-carboxymethyl-phenyl)-carbamoylmethyl-3,6,9-triazaundecanedioicacid

1.053 g (2 mmol) of the substance produced according to part b) isheated in 50 ml of water with 362 mg (1 mmol) of gadolinium oxide for 1hour to 80°-85° C. In this case, the oxide goes into solution. It isfiltered by a 0.1 micron membrane filter and the substance is isolatedby freeze-drying. 1.35 g of the title compound is obtained as a whitepowder.

Analysis (relative to the anhydrous substance): Calculated: C 38.82 H4.00 Gd 23.10 N 8.23; C 38.57 H 4.40 Gd 22.95 N 8.33

Example 3

a) 6-Carboxymethyl-9-4-(carboxyisopropyl)-phenyl!-carbamoylmethyl-3-ethoxycarbonylmethyl-3,6,9-triazaundecanedioicacid

Analogously to Example 2a, the title compound is obtained from N³-(2,6-dioxomorpholinoethyl)-N⁶-(ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid andalpha,alpha-dimethyl-p-aminophenylacetic acid.

Analysis (relative to the anhydrous substance): Calculated: C 53.60 H6.57 N 6.92; C 53.44 H 6.88 N 9.49

b) 3,6-Bis(carboxymethyl)-9-4-(carboxyisopropyl)-phenyl!-carbamoylmethyl-3,6,9-triazaundecanedioicacid

Analogously to Example 2b, the title compound is obtained by alkalinesaponification of 6-carboxymethyl-9-4-(carboxyisopropyl)-phenyl!-carbamoylmethyl-3-ethoxycarbonylmethyl-3,6,9-triazaundecanedioicacid.

Analysis (relative to the anhydrous substance): Calculated: C 51.98 H6.18 N 10.10; C 51.79 H 6.35 N 10.01

c) Gadolinium complex of 3,6-bis(carboxymethyl)-9-4-(carboxyisopropyl)-phenyl!-carbamoylmethyl-3,6,9-triazaundecanedioicacid

Analogously to Example 2c, the title compound is obtained by complexingof the ligand with gadolinium oxide.

Analysis (relative to the anhydrous substance): Calculated: C 40.67 H4.41 Gd 22.19 N 7.90; C 40.47 H 4.60 Gd 22.01 N 7.80

Example 4

a)3,6-Bis(carboxymethyl)-9-(11-carboxy-1-n-hexyl-undecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid

15.33 g (38 mmol) of N³ -(2,6-dioxomorpholinoethyl)-N⁶-(ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid (Example 13a of EP 0331 616) is suspended in 100 ml of dimethylformamide and mixed in an icebath with 21.07 ml (152 mmol) of triethylamine and 11.36 g (38 mmol) of12-aminooctadecanoic acid. After stirring overnight at room temperature,it is concentrated by evaporation in a vacuum, and the residue isabsorptively precipitated with 500 ml of diethyl ether. It is suctionedoff and the dried reaction product is dissolved in 50 ml of 2 n sodiumhydroxide solution. After three hours of stirring, it is neutralizedwith dilute hydrochloric acid, evaporated to dryness in a vacuum andrecrystallized from water. 15.64 g (61% of theory) of a gray powder isobtained.

Analysis (relative to the anhydrous substance): Calculated: C 56.95 H8.66 N 8.30; C 56.87 H 8.77 N 8.35

b) Gadolinium complex of3,6-bis(carboxymethyl)-9-(11-carboxy-1-n-hexyl-undecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid

10.12 g (15 mmol) of the above-described compound is suspended in 200 mlof water and mixed with 2.72 g (7.5 mmol) of gadolinium oxide. It isheated for 60 minutes to 90° C., allowed to cool off to roomtemperature, filtered, and the solution is freeze-dried. 12.43 g(quantitative) of the title compound is obtained as a white powder.

Analysis (relative to the anhydrous substance): Calculated: C 46.36 H6.69 N 6.76 Gd 18.97; C 46.31 H 6.75 N 6.68 Gd 18.95

The substance forms associates in aqueous solution with human serumalbumin.

Example 5

a)3,6-Bis(carboxymethyl)-9-(10-carbethoxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid

17.85 g (50 mmol) of1.5-bis(2,6-dioxomorpholino)-3-carboxymethyl-3-azapentane is stirred in200 ml of dimethylformamide and mixed with 9 ml (50 mmol) of water. Thesolution is heated for 3 hours to 70° C., cooled off to 0° C. and 36.07ml (260 mmol) of triethylamine and 10.8 g (50 mmol) of11-aminoundecanoic acid ethyl ester are added. After stirring overnightat room temperature, the solution is evaporated to dryness in a vacuum.The residue is taken up in 100 ml of water and the solution is mixed bydrops with concentrated hydrochloric acid until permanent cloudiness.After stirring overnight in the ice bath, the finely crystallineprecipitate is suctioned off, washed with water and dried in a vacuum at50° C. 14.9 g (65% of theory) of the title compound is obtained as awhite powder with melting point 155°-157° C.

Analysis (relative to the anhydrous substance): Calculated: C 53.63 H8.00 N 9.27; C 53.58 H 8.22 N 9.41

b) Gadolinium complex of3,6-bis(carboxymethyl)-9-(10-carbethoxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid

9.08 g (15 mmol) of the compound described in Example 5a) is suspendedin 200 ml of water, mixed with 2.72 g (7.5 mmol) of Gd₂ O₃ and broughtto clear solution with stirring at room temperature. By freeze-drying,the gadolinium complex is obtained as white powder in quantitativeyield.

Analysis (relative to the anhydrous substance): Calculated: C 42.73 H5.98 N 7.38 Gd 20.72; C 42.80 H 5.87 N 7.51 Gd 20.63

Example 6

a)1,5-Bis(2,6-dioxomorpholino)-2-(4-ethoxybenzyl)-3-carboxymethyl-3-azapentane

52.8 g (100 mmol) of3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioicacid, produced according to EP publication no. 0 405 704 Example 8b)!,is suspended in 75 ml of acetic anhydride. 38 ml of pyridine is addedand heated for 3 hours to 50° C. After cooling off to room temperatureand stirring overnight, the precipitate is suctioned off, washed threetimes with 200 ml of diethyl ether each and dried in a vacuum at 30° C.40.3 g (82% of theory) of the title compound is obtained as a whitepowder with melting point 172°-174° C.

Analysis Calculated: C 56.21 H 5.95 N 8.55; C 56.35 H 5.88 N 8.60

b)3,6-Bis(carboxymethyl)-4-(4-ethoxybenzyl-9-(10-carboxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid and6,9-bis(carboxymethyl)-4-(4-ethoxybenzyl-3-(10-carboxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid

24.6 g (50 mmol) of the compound obtained according to Example 6a) isstirred in 200 ml of dimethylformamide and mixed with 9 ml (50 mmol) ofwater. The solution is heated for 3 hours to 70° C., cooled off to 0° C.and 36.07 ml (260 mmol) of triethylamine and 10.0 g (50 mmol) of11-aminoundecanoic acid are added. After stirring overnight at roomtemperature, the solution is evaporated to dryness in a vacuum. Theresidue is taken up in 500 ml of water and mixed by instillation withconcentrated hydrochloric acid until permanent cloudiness. Afterstirring overnight in the ice bath, the precipitate is suctioned off,washed with water and dried in a vacuum at 50° C. 21.3 g (60% of theory)of the isomer mixture is obtained as a white powder with melting point184°-186° C.

Analysis (relative to the anhydrous substance): Calculated: C 57.45 H7.66 N 7.88; C 57.38 H 7.80 N 7.95

c) Gadolinium complex of3,6-bis(carboxymethyl)-4-(4-ethoxybenzyl)-9-(10-carboxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid and6,9-bis(carboxymethyl)-4-(4-ethoxybenzyl)-3-(10-carboxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid

10.65 g (15 mol) of the complexing agent described in Example 6b) issuspended in 200 ml. of water and mixed with 2.72 g (7.5 mmol) of Gd₂O₃. It is heated for 1 hour to 90° C., the solution is added by amembrane filter and the complexes are isolated as a white powder byfreeze-drying in quantitative yield.

Analysis (relative to the anhydrous substance): Calculated: C 47.20 H5.94 N 6.48 Gd 18.18; C 47.15 H 5.73 N 6.39 Gd 18.30

Example 7

a) 3,6,9-tris-Carboxymethyl-3,6,9-triazaundecanedioic acid-N-methyl-N'-(4-carboxyphenyl)!monoamide

15.33 g (38 mmol) of N³ -(2,6-dioxomorpholinoethyl)-N⁶-(ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid Example 13a) of EP 0331 616! is suspended in 100 ml of dimethylformamide and mixed at 0° C.with 21 ml of triethylamine and 5.74 g (38 mmol) of4-N-methylaminobenzoic acid. After stirring overnight at roomtemperature, it is evaporated to dryness in a vacuum, and the residue isabsorptively precipitated with 500 ml of diethyl ether. It is suctionedoff and, after recrystallization from ethanol, 11.9 g (60% of theory) ofthe title compound is obtained as a white powder.

Analysis Calculated: C 50.28 H 5.56 N 10.66; C 50.35 H 5.61 N 10.58

b) Gadolinium complex of3,6,9-tris-carboxymethyl-3,6,9-triazaundecanedioic acidN-methyl-N'-(4-carboxyphenyl!monoamide

7.88 g (15 mmol) of the above-described compound is suspended in 200 mlof water and mixed with 2.72 g (7.5 mmol) of Gd₂ O₃. It is heated for 60minutes to 90° C., allowed to cool off to room temperature and thesolution is freeze-dried. The title compound is obtained as a whitepowder with an uncharacteristic decomposition point in quantitativeyield.

Analysis (relative to the anhydrous substance): Calculated: C 38.87 H3.86 N 8.24 Gd 23.13; C 38.81 H 3.94 N 8.31 Gd 23.25

Examples for the Form of Administration

Production of a solution of the gadolinium complex of3,6-bis(carboxymethyl)-9-(10-carboxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid

365.43 g (0.5 mol) of the compound described in Example 1b is dissolvedwith adding 195.22 g (1 mol) of N-methylglucamine in 600 ml of water perinjection (p.i.). After adding 3.22 g of monohydrate of the calciumtrisodium salt of the DTPA, CaNa₃ DTPA and 1.21 g oftrishydroxymethylaminomethane are adjusted with dilute hydrochloric acidto pH 7.0 and filled up with water p.i. to 1000 ml. The solution isultrafiltered, bottled in flasks and heat-sterilized.

Composition of a Powder for Oral Administration

12.8 g (35 mmol) of the compound described in Example 1b; 12.0 g ofsucrose; 0.5 g of polyoxyethylenepolyoxypropylene polymer; 0.001 g ofaromatic substances

Example for an In Vivo NMR Diagnosis

A cell suspension of the Brown-Pearce tumor was injected in the liver ina test animal (rat, strain lew/mol, female, 155 g) two weeks before thetest. In the method used, about 2 weeks were required until the tumorhad reached the size of 0.5-1 cm³ desired for the test.

For the test, the animal was anesthetized (Rompun+Ketavet) and then acatheter was placed in the caudal vein for the administration of thecontrast medium.

The imaging took place in an MRI experimental device of the GeneralElectric company (field strength 2 teslas). The first image was madewithout contrast media with a T₁ -weighted spin echo sequence (TR=400msec, TE=20 msec, layer thickness 3 mm). The liver appears with theexpected (normal) signal intensity; the tumor is isodense and cannot bedefined. Then, the administration of the contrast medium gadoliniumcomplex of3,6-bis(carboxymethyl)-9-(10-carboxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid, Example 1b)! took place through the vein catheter with a dose of0.1 mmol of Gd/kg (concentration of the solution of 0.05 mmol/ml in 0.9%NaCl, i.e. a clinically usual dose, e.g., in the case of the commercialpreparation Magnevist®). Image no. 2 was taken 60 minutes after theadministration of the contrast medium under conditions which wereotherwise the same as image no. 1. The liver parenchyma now appears verybright and the tumor, which is considerably darker in comparison withthe surrounding liver tissue, can be discerned clearly. This means thatthe contrast medium is concentrated in the liver to a great extent, but,not in the tumor. In this respect, a considerable advantage is offeredhere for the diagnosis of liver tumors relative to the previous singlecontrast medium Magnevist®, found on the market, for the nuclear spintomography.

Based on the very strong enhancement of the stomach in image no. 2, itis further shown that the substance is obviously also secreted in thestomach. This offers further diagnostic possibilities with respect to abetter differentiation of liver and stomach.

In another animal (rat, strain Lew/mol, female, 200 g), the samecontrast medium was administered orally with a p.o. sample in a dose of0.5 mmol of Gd/kg (concentration of the solution 0.033 mmol of Gd/ml, in0.9% NaCl). The animal was anesthetized 30 minutes after theadministration and examined under the same conditions as described inthe first case. As early as 45 minutes (image 3) after theadministration, a slight increase in the signal in the liver becomesapparent. A marked enhancement in the liver can be discerned 180 minutesafter administration (image 4) which suggests that the substance isresorbed in the small intestine after oral administration and isimmediately taken up again for the most part by the liver. This findingagrees very well with the pharmacokinetic data. Thus it follows that aliver tumor diagnosis is possible also with an oral administration ofthe contrast medium.

KEY:

Bild 1=Image 1

Bild 2=Image 2

Bild 3=Image 3

Bild 4=Image 4

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. In a method of NMR imaging comprising imaging apatient to whom a contrast agent has been administered, the improvementwherein said contrast agent is a physiologically acceptable chelatecompound of formula I ##STR6## wherein Z¹ and Z² are each,independently, H or--(CH₂)_(m) --(C₆ H₄)_(q) --(O)_(k) --(CH₂)_(n) --(C₆H₄)_(l) --(O)_(r) --R, m and n are each independently 0-20, k, l, q andr are each independently 0 or 1, and R is H, C₁ -C₆ -alkyl, C₁ -C₆-alkyl substituted by OR¹, or CH₂ COOR¹, R¹ is H, C₁ -C₆ -alkyl, orbenzyl, R² is a saturated, unsaturated, straight-chain or branched-chainor cyclic non-aromatic hydrocarbyl group with up to 20 C-atoms which issubstituted by a carboxyl group, a sulfone group, a carboxyl groupesterified with C₁ -C₆ -alkyl or benzyl, or a sulfone group esterifiedwith C₁ -C₆ -alkyl or benzyl,an aryl group of up to 10 C-atomssubstituted by a carboxyl group, a sulfone group, a carboxyl groupesterified with C₁ -C₆ -alkyl or benzyl or a sulfone group esterifiedwith C₁ -C₆ -alkyl or benzyl, or an aralkyl group of up to 16 C-atomssubstituted by a carboxyl group, a sulfone group, a carboxyl groupesterified with C₁ -C₆ -alkyl or benzyl, or a sulfone group esterifiedwith C₁ -C₆ -alkyl or benzyl, R³ is H or a saturated, unsaturated,straight-chain or branched-chain or cyclic non-aromatic hydrocarbylgroup with up to 20 C-atoms, which is optionally substituted by acarboxyl group, a sulfone group, a carboxyl group esterified with C₁ -C₆-alkyl or benzyl, or a sulfone group esterified with C₁ -C₆ -alkyl orbenzyl, an aryl group of up to 10 C-atoms which is optionallysubstituted by a carboxyl group, a sulfone group, a carboxyl groupesterified with C₁ -C₆ -alkyl or benzyl, or a sulfone group esterifiedwith C₁ -C₆ -alkyl or benzyl, or an aralkyl group of up to 16 C-atomsoptionally substituted by a carboxyl group, a sulfone group, a carboxylgroup esterified with C₁ -C₆ -alkyl or benzyl, or a sulfone groupesterified with C₁ -C₆ -alkyl or benzyl, X is H and/or a metal ionequivalent of an element of atomic numbers 21-29, 31, 32, 37-40, 42-44,49 or 57-83, wherein acid groups are, in each case, optionally presentas an ester with C₁ -C₆ -alkyl, benzyl or 4-methoxybenzyl, or as anamide wherein the nitrogen atom of said amide is substituted by at leastone saturated or unsaturated straight-chain, branched-chain or cyclichydrocarbon radical with up to 5 C atoms, wherein said at least onehydrocarbon radical is optionally substituted by 1-3 hydroxy groupsand/or 1-3 C₁ -C₄ -hydroxy groups, or said amide is in the form of a 5-or 6-membered heterocyclic ring with inclusion of the amide nitrogenatom; or a salt thereof with an inorganic and/or organic base, an aminoacid or an amino acid amide, wherein at least two of substituents X aremetal ion equivalents of at least one element of atomic numbers 21-29,42, 44 or 58-70, at least one of substituents Z¹ and Z² is H, and, if nand l are each 0, then k and r are not both
 1. 2. A method according toclaim 1, wherein Z¹ and Z² each stand for a hydrogen.
 3. A methodaccording to claim 1, wherein Z¹ stands for a hydrogen atom and Z²stands for the radical --(CH₂)_(m) --(C₆ H₄)_(q) --(O)_(k) --(CH₂)_(n)--(C₆ H₄)_(l) --(O)_(r) --R.
 4. A method according to claim 1, whereinZ² stands for a hydrogen atom and Z¹ stands for the radical --(CH₂)_(m)--(C₆ H₄)_(q) --(O)_(k) --(CH₂)_(n) --(C₆ H₄)_(l) --(O)_(r) --R.
 5. Amethod according to claim 1, wherein Z¹ or Z² stand for the radicals--CH₂ --C₆ H₄ --OH, --CH₂ --C₆ H₄ --OCH₃, --CH₂ C₆ H₅, --CH₂ --C₆ H₄--O--CH₂ --C₆ H₄ --OCH₃, --CH₂ --O--CH₂ --C₆ H₅, --CH₂ --C₆ H₄ --O--CH₂--COOH, --CH₂ --C₆ H₄ --OC₂ H₅, --CH₂ --C₆ H₄ --OC₄ H₉, --CH₂ --C₆ H₄--O--CH₂ --C₆ H₅.
 6. A method according to claim 1, wherein R³ standsfor the methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, phenyl,benzyl, 4-carboxy-phenylene, 1-cyclohexyl-1-carboxylic acid,1-cyclopentyl-1-carboxylic acid, 2-carboxy-phenylene,11-carboxy-1-undecyl, 10-carboxy-1-decyl, 7-carboxy-1-heptyl,6-carboxy-1-hexyl, 5-carboxy-1-pentyl, 4-carboxy-benzyl,4-carboxy-1-cyclohexylmethyl, 4-carboxymethyl-phenylene,4-(1,1-dimethylcarboxymethylene)-phenylene, 4-sulfophenylene,10-sulfo-1-decyl, 8-sulfo-1-octyl, 17-carboxy-7-heptadecyl,7-carboxy-2-heptyl, 1-carboxy-4-phenyl-2-propyl, 2-carboxyethyl,4-carboxy-4-but-1-enyl radical.
 7. A method according to claim 1,wherein the patient's gastrointestinal tract, renal system and/orhepatobiliary system is imaged.
 8. A compound according to claim 1,wherein one COOX group is present as an amide.
 9. A method according toclaim 1, wherein said compound is a gadolinium complex of3,6-bis(carboxymethyl)-9-(10-carboxydecylcarbamoylmethyl)-3,6,9-triazaundecanedioicacid.
 10. A method according to claim 9, wherein a portion of thepatient's hepatobiliary system is imaged.
 11. A method of X-ray imagingcomprising imaging a patient to whom a contrast agent has beenadministered, the improvement wherein said contrast agent is aphysiologically acceptable chelate compound of formula I ##STR7##wherein Z¹ and Z² are each independently H or --(CH₂)_(m) --(C₆ H₄)_(q)--(O)_(k) --(CH₂)_(n) --(C₆ H₄)_(l) --(O)_(r) --R,m and n are eachindependently 0-20, k, l, q and r are each independently 0 or 1, and Ris H, C₁ -C₆ -alkyl, C₁ -C₆ -alkyl substituted by OR¹, or CH₂ COOR¹, R¹is H, C₁ -C₆ -alkyl, or benzyl, R² is a saturated, unsaturated,straight-chain or branched-chain or cyclic non-aromatic hydrocarbylgroup with up to 20 C-atoms which is substituted by a carboxyl group, asulfone group, a carboxyl group esterified with C₁ -C₆ -alkyl or benzyl,or a sulfone group esterified with C₁ -C₆ -alkyl or benzyl,an aryl groupof up to 10 C-atoms substituted by a carboxyl group, a sulfone group, acarboxyl group esterified with C₁ -C₆ -alkyl or benzyl or a sulfonegroup esterified with C₁ -C₆ -alkyl or benzyl, or an aralkyl group of upto 16 C-atoms substituted by a carboxyl group, a sulfone group, acarboxyl group esterified with C₁ -C₆ -alkyl or benzyl, or a sulfonegroup esterified with C₁ -C₆ -alkyl or benzyl, R³ is H or a saturated,unsaturated, straight-chain or branched-chain or cyclic non-aromatichydrocarbyl group with up to 20 C-atoms, which is optionally substitutedby a carboxyl group, a sulfone group, a carboxyl group esterified withC₁ -C₆ -alkyl or benzyl, or a sulfone group esterified with C₁ -C₆-alkyl or benzyl,an aryl group of up to 10 C-atoms which is optionallysubstituted by a carboxyl group, a sulfone group, a carboxyl groupesterified with C₁ -C₆ -alkyl or benzyl, or a sulfone group esterifiedwith C₁ -C₆ -alkyl or benzyl, or an aralkyl group of up to 16 C-atomsoptionally substituted by a carboxyl group, a sulfone group, a carboxylgroup esterified with C₁ -C₆ -alkyl or benzyl, or a sulfone groupesterified with C₁ -C₆ -alkyl or benzyl, X is H and/or a metal ionequivalent of an element of atomic numbers 21-29, 31, 32, 37-40, 42-44,49 or 57-83, wherein acid groups are, in each case, optionally presentas an ester with C₁ -C₆ -alkyl, benzyl or 4-methoxybenzyl, or as anamide wherein the nitrogen atom of said amide is substituted by at leastone saturated or unsaturated straight-chain, branched-chain or cyclichydrocarbon radical with up to 5 C atoms, wherein said at least onehydrocarbon radical is optionally substituted by 1-3 hydroxy groupsand/or 1-3 C₁ -C₄ -hydroxy groups, or said amide is in the form of a 5-or 6-membered heterocyclic ring with inclusion of the amide nitrogenatom; or a salt thereof with an inorganic and/or organic base, an aminoacid or an amino acid amide, wherein at least two of substituents X aremetal ion equivalents of at least one element of atomic numbers 21-29,42, 44 or 57-83, at least one of substituents Z¹ and Z² is H, and, if nand l are each 0, then k and r are not both
 1. 12. A method ofradiodiagnostic imaging comprising imaging a patient to whom a contrastagent has been administered, the improvement wherein said contrast agentis a physiologically acceptable chelate compound of formula I ##STR8##wherein Z¹ and Z² are each, independently, H or --(CH₂)_(m) --(C₆H₄)_(q) --(O)_(k) --(CH₂)_(n) --(C₆ H₄)_(l) --(O)_(r) --R,m and n areeach independently 0-20, k, l, q and r are each independently 0 or 1,and R is H, C₁ -C₆ -alkyl, C₁ -C₆ -alkyl substituted by OR¹, or CH₂COOR¹, R¹ is H, C₁ -C₆ -allyl, or benzyl, R² is a saturated,unsaturated, straight-chain or branched-chain or cyclic non-aromatichydrocarbyl group with up to 20 C-atoms which is substituted by acarboxyl group, a sulfone group, a carboxyl group esterified with C₁ -C₆-alkyl or benzyl, or a sulfone group esterified with C₁ -C₆ -alkyl orbenzyl,an aryl group of up to 10 C-atoms substituted by a carboxylgroup, a sulfone group, a carboxyl group esterified with C₁ -C₆ -alkylor benzyl or a sulfone group esterified with C₁ -C₆ -alkyl or benzyl, oran aralkyl group of up to 16 C-atoms substituted by a carboxyl group, asulfone group, a carboxyl group esterified with C₁ -C₆ -alkyl or benzyl,or a sulfone group esterified with C₁ -C₆ -alkyl or benzyl, R³ is H or asaturated, unsaturated, straight-chain or branched-chain or cyclicnon-aromatic hydrocarbyl group with up to 20 C-ators, which isoptionally substituted by a carboxyl group, a sulfone group, a carboxylgroup esterified with C₁ -C₆ -alkyl or benzyl, or a sulfone groupesterified with C₁ -C₆ -alkyl or benzyl,an aryl group of up to 10C-atoms which is optionally substituted by a carboxyl group, a sulfonegroup, a carboxyl group esterified with C₁ -C₆ -alkyl or benzyl, or asulfone group esterified with C₁ -C₆ -alkyl or benzyl, or an aralkylgroup of up to 16 C-atoms optionally substituted by a carboxyl group, asulfone group, a carboxyl group esterified with C₁ -C₆ -alkyl or benzyl,or a sulfone group esterified with C₁ -C₆ -alkyl or benzyl, X is Hand/or a metal ion equivalent of a radionuclide of atomic numbers 27,29, 31, 32, 37-39, 43, 49, 62, 64, 70 or 77 wherein acid groups are, ineach case, optionally present as an ester with C₁ -C₆ -alkyl, benzyl or4-methoxybenzyl, or as an amide wherein the nitrogen atom of said amideis substituted by at least one saturated or unsaturated straight-chain,branched-chain or cyclic hydrocarbon radical with up to 5 C atoms,wherein said at least one hydrocarbon radical is optionally substitutedby 1-3 hydroxy groups and/or 1-3 C₁ -C₄ -hydroxy groups, or said amideis in the form of a 5- or 6-membered heterocyclic ring with inclusion ofthe amide nitrogen atom; or a salt thereof with an inorganic and/ororganic base, an amino acid or an amino acid amide, wherein at least oneof substituents Z¹ and Z² is H, and, if n and l are each 0, then k and rare not both
 1. 13. In a method of radiation therapy comprisingadministering a radiotherapeutic agent to a patient, the improvementwherein said agent is a physiologically acceptable chelate compound offormula I ##STR9## wherein Z¹ and Z² are each independently H or--(CH₂)_(m) --(C₆ H₄)_(q) --(O)_(k) --(CH₂)_(n) --(C₆ H₄)_(l) --(O)_(r)--R,m and n are each independently 0-20, k, l, q and r are eachindependently 0 or 1, and R is H, C₁ -C₆ -alkyl, C₁ -C₆ -alkylsubstituted by OR¹, or CH₂ COOR¹, R¹ is H, C₁ -C₆ -alkyl, or benzyl, R²is a saturated, unsaturated, straight-chain or branched-chain or cyclicnon-aromatic hydrocarbyl group with up to 20 C-atoms which issubstituted by a carboxyl group, a sulfone group, a carboxyl groupesterified with C₁ -C₆ -alkyl or benzyl, or a sulfone group esterifiedwith C₁ -C₆ -alkyl or benzyl,an aryl group of up to 10 C-atomssubstituted by a carboxyl group, a sulfone group, a carboxyl groupesterified with C₁ -C₆ -alkyl or benzyl or a sulfone group esterifiedwith C₁ -C₆ -alkyl or benzyl, or an aralkyl group of up to 16 C-atomssubstituted by a carboxyl group, a sulfone group, a carboxyl groupesterified with C₁ -C₆ -alkyl or benzyl, or a sulfone group esterifiedwith C₁ -C₆ -alkyl or benzyl, R³ is H or a saturated, unsaturated,straight-chain or branched-chain or cyclic non-aromatic hydrocarbylgroup with up to 20 C-atoms, which is optionally substituted by acarboxyl group, a sulfone group, a carboxyl group esterified with C₁ -C₆-alkyl or benzyl, or a sulfone group esterified with C₁ -C₆ -alkyl orbenzyl,an aryl group of up to 10 C-atoms which is optionally substitutedby a carboxyl group, a sulfone group, a carboxyl group esterified withC₁ -C₆ -alkyl or benzyl, or a sulfone group esterified with C₁ -C₆-alkyl or benzyl, or an aralkyl group of up to 16 C-atoms optionallysubstituted by a carboxyl group, a sulfone group, a carboxyl groupesterified with C₁ -C₆ -alkyl or benzyl, or a sulfone group esterifiedwith C₁ -C₆ -alkyl or benzyl, X is H and/or a metal ion equivalent of anelement of atomic numbers 21-29, 31, 32, 37-40, 42-44, 49 or 57-83,wherein acid groups are, in each case, optionally present as an esterwith C₁ -C₆ -alkyl, benzyl or 4-methoxybenzyl, or as an amide whereinthe nitrogen atom of said amide is substituted by at least one saturatedor unsaturated straight-chain, branched-chain or cyclic hydrocarbonradical with up to 5 C atoms, wherein said at least one hydrocarbonradical is optionally substituted by 1-3 hydroxy groups and/or 1-3 C₁-C₄ -hydroxy groups, or said amide is in the form of a 5- or 6-memberedheterocyclic ring with inclusion of the amide nitrogen atom; or a saltthereof with an inorganic and/or organic base, an amino acid or an aminoacid amide, wherein at least one radionuclide is an element of atomicnumbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70 or 77, at least one ofsubstituents Z¹ and Z² is H, and, if n and l are each 0, then k and rare not both
 1. 14. A method according to claim 1, wherein R² is4-carboxy-phenylene, 1-cyclohexyl-1-carboxylic acid,1-cyclopentyl-1-carboxylic acid, 2-carboxy-phenylene,11-carboxy-1-undecyl, 10-carboxy-1-decyl, 7-carboxy-1-heptyl,6-carboxy-1-hexyl, 5-carboxy-1-pentyl, 4-carboxy-benzyl,4-carboxy-1-cyclohexylmethyl, 4-carboxymethyl-phenylene,4-(1,1-dimethylcarboxymethylene)-phenylene, 4-sulfophenylene,10-sulfo-1-decyl, 8-sulfo-1-octyl, 17-carboxy-7-heptadecyl,7-carboxy-2-heptyl, 1-carboxy-4-phenyl-2-propyl, 2-carboxyethyl, or4-carboxy-4-but-1-enyl.
 15. A method according to claim 6, wherein R² is4-carboxy-phenylene, 1-cyclohexyl-1-carboxylic acid,1-cyclopentyl-1-carboxylic acid, 2-carboxy-phenylene,11-carboxy-1-undecyl, 10-carboxy-1decyl, 7-carboxy-1-heptyl,6-carboxy-1-hexyl, 5-carboxy-1-pentyl, 4-carboxy-benzyl,4-carboxy-1-cyclohexylmethyl, 4-carboxymethyl-phenylene,4-(1,1-dimethylcarboxymethylene)-phenylene, 4-sulfophenylene,10-sulfo-1-decyl, 8-sulfo-1-octyl, 17-carboxy-7-heptadecyl,7-carboxy-2-heptyl, 1-carboxy-4-phenyl-2-propyl, 2-carboxyethyl, or4-carboxy-4-but-1-enyl.
 16. In a method of NMR imaging comprisingimaging a patient to whom a contrast agent has been administered, theimprovement wherein:the patient's gastrointestinal tract, renal system,and/or hepatobiliary system is imaged, and said contrast agent is aphysiologically acceptable chelate compound of formula ##STR10## whereinZ¹ and Z² are each, independently, H or --(CH₂)_(m) --(C₆ H₄)_(q)--(O)_(k) --(CH₂)_(n) --(C₆ H₄)_(l) --(O)_(r) --R, m and n are eachindependently 0-20, k, l, q and r are each independently 0 or 1, and Ris H, C₁ -C₆ -alkyl, C₁ -C₆ -alkyl substituted by OR¹, or CH₂ COOR¹, R¹is H, C₁ -C₆ -alkyl, or benzyl, R² is a saturated, unsaturated,straight-chain or branched-chain or cyclic non-aromatic hydrocarbylgroup with up to 20 C atoms which is substituted by a carboxyl group, asulfone group, a carboxyl group esterified with C₁ -C₆ -alkyl or benzyl,or a sulfone group esterified with C₁ -C₆ -alkyl or benzyl,an aryl groupof up to 10 C atoms substituted by a carboxyl group, a sulfone group, acarboxyl group esterified with C₁ -C₆ -alkyl or benzyl or a sulfonegroup esterified with C₁ -C₆ -alkyl or benzyl, or an aralkyl group of upto 16 C atoms substituted by a carboxyl group, a sulfone group, acarboxyl group esterified with C₁ -C₆ -alkyl or benzyl, or a sulfonegroup esterified with C₁ -C₆ -alkyl or benzyl, R³ is H or a saturated,unsaturated, straight-chain or branched-chain or cyclic non-aromatichydrocarbyl group with up to 20 C atoms, which is substituted by acarboxyl group, a sulfone group, a carboxyl group esterified with C₁ -C₆-alkyl or benzyl, or a sulfone group esterified with C₁ -C₆ -alkyl orbenzyl,an aryl group of up to 10 C atoms which is substituted by acarboxyl group, a sulfone group, a carboxyl group esterified with C₁ -C₆-alkyl or benzyl, or a sulfone group esterified with C₁ -C₆ -alkyl orbenzyl, or an aralkyl group of up to 16 C atoms substituted by acarboxyl group, a sulfone group, a carboxyl group esterified with C₁ -C₆-alkyl or benzyl, or a sulfone group esterified with C₁ -C₆ -alkyl orbenzyl, X is H and/or a metal ion equivalent of an element of atomicnumbers 21-29, 31, 32, 37-40, 42-44, 49 or 57-83, wherein acid groupsare, in each case, optionally present as an ester, or as an amide; asalt thereof with an inorganic and/or organic base, an amino acid or anamino acid amide, wherein at least two of substituents X are metal ionequivalents of at least one element of atomic numbers 21-29, 42, 44 or58-70, at least one of substituents Z¹ and Z² is H, and, if n and l areeach 0, then k and r are not both
 1. 17. A method according to claim 16,wherein one of Z¹ and Z² is H and the other is --CH₂ --C₆ H₄ --OH, --CH₂--C₆ H₄ --OCH₃, --CH₂ C₆ H₅, --CH₂ --C₆ H₄ --O--CH₂ --C₆ H₄ --OCH₃,--CH₂ --O--CH₂ --C₆ H₅, --CH₂ --C₆ H₄ --O--CH₂ --COOH, --CH₂ --C₆ H₄--OC₂ H₅, --CH₂ --C₆ H₄ --OC₄ H₉, --CH₂ --C₆ H₄ --O--CH₂ --C₆ H₅.
 18. Amethod according to claim 16, wherein R³ stands for the methyl, ethyl,propyl, isopropyl, butyl, pentyl, hexyl, phenyl, benzyl,4-carboxy-phenylene, 1-cyclohexyl-1-carboxylic acid,1-cyclopentyl-1-carboxylicacid, 2-carboxy-phenylene,11-carboxy-1-undecyl, 10-carboxy-1-decyl, 7-carboxy-1-heptyl,6-carboxy-1-hexyl, 5-carboxy-1-pentyl, 4-carboxybenzyl,4-carboxy-1-cyclohexylmethyl, 4-carboxymethyl-phenylene,4-(1,1-dimethylcarboxymethylene)-phenylene, 4-sulfophenylene,10-sulfo-1-decyl, 8-sulfo-1-octyl, 17-carboxy-7-heptadecyl,7-carboxy-2-heptyl, 1-carboxy-4-phenyl-2-propyl, 2-carboxyethyl,4-carboxy-4-but-1-enyl radical.